chrX-83508515-G-A

Variant names:

• chrX-83508515-G-A
• rs753206337
• NM_000307.5:c.191G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_000307.5(POU3F4):​c.191G>A​(p.Gly64Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000459 in 1,089,456 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: POU3F4 NM_000307.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.72

Genes affected

POU3F4 (HGNC:9217): (POU class 3 homeobox 4) This gene encodes a member of the POU-III class of neural transcription factors. This family member plays a role in inner ear development. The protein is thought to be involved in the mediation of epigenetic signals which induce striatal neuron-precursor differentiation. Mutations in this gene are associated with X chromosome-linked nonsyndromic mixed deafness. [provided by RefSeq, Dec 2012]

ENSG00000279437 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-83508515-G-A is Pathogenic according to our data. Variant chrX-83508515-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3250397.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27950913). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU3F4	NM_000307.5	c.191G>A	p.Gly64Glu	missense_variant	Exon 1 of 1	ENST00000644024.2	NP_000298.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU3F4	ENST00000644024.2	c.191G>A	p.Gly64Glu	missense_variant	Exon 1 of 1		NM_000307.5	ENSP00000495996.1
ENSG00000279437	ENST00000625081.1	n.700C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000125 AC: 2 AN: 159911 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 50055

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000392

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000146

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000459 AC: 5 AN: 1089456 Hom.: 0 Cov.: 31 AF XY: 0.00000281 AC XY: 1 AN XY: 356328

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000293

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000239

Gnomad4 OTH exome AF: 0.0000437

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked mixed hearing loss with perilymphatic gusher Pathogenic:1

Jun 05, 2024

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

A very rare variant predicted to be deleterious by most prediction programs -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.98
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	0.031	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.025	D;.
Vest4		0.41
MutPred		0.20		Gain of solvent accessibility (P = 0.0374);Gain of solvent accessibility (P = 0.0374);
MVP		0.93
MPC		1.6
ClinPred		0.49	T
GERP RS		4.8
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs753206337; hg19: chrX-82763523; COSMIC: COSV64541677;